The effects of zolpidem treatment on GABAA receptors in cultured cerebellar granule cells: Changes in functional coupling

Vlainić, Josipa; Štrac, Dubravka Švob; Jembrek, Maja Jazvinšćak; Vlainić, Toni; Peričić, Danka

doi:10.1016/j.lfs.2012.04.021

Cited by 8 publications

(8 citation statements)

References 40 publications

(66 reference statements)

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“…Although the number of pharmacological studies on the dependence/tolerance of zolpidem is very limited, it is likely appropriate to interpret its potential mechanisms based on studies of benzodiazepine tolerance solely because the GABA receptor is the major targeted receptor for both zolpidem and benzodiazepines. There are five potential mechanisms underlying the influences of long-term benzodiazepine exposure ( 53 , 54 ). First, a change in GABA A receptor gene expression, which might be related to the exposure time ( 55 ), might result in the development of tolerance, although most reports suggested that the number of GABA A receptors might not change because of the maximal binding capacity (B max ) of [ 3 H] flunitrazepam (a non-selective benzodiazepine) did not change significantly during the studied periods ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

“…There are five potential mechanisms underlying the influences of long-term benzodiazepine exposure ( 53 , 54 ). First, a change in GABA A receptor gene expression, which might be related to the exposure time ( 55 ), might result in the development of tolerance, although most reports suggested that the number of GABA A receptors might not change because of the maximal binding capacity (B max ) of [ 3 H] flunitrazepam (a non-selective benzodiazepine) did not change significantly during the studied periods ( 54 ). Second, the changes in the subunit composition of GABA A receptors might influence the binding of drugs to receptors, especially any changes in the expression of γ submit or α submit ( 53 , 54 ).…”

Section: Discussionmentioning

confidence: 99%

“…Second, the changes in the subunit composition of GABA A receptors might influence the binding of drugs to receptors, especially any changes in the expression of γ submit or α submit ( 53 , 54 ). Third, uncoupling of the GABA and benzodiazepine binding sites may reduce benzodiazepine activity ( 53 , 54 ). Vlainić et al documented that the number of functional interactions occurring at GABA A receptors in the zolpidem group was diminished by approximately 40% of the control values ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

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Case report: Chronological symptom profile after cessation of overdose zolpidem in a patient with comorbid bipolar disorder—from anxiety, craving, paresthesia and influenza-like symptoms to seizures and hallucinations

et al. 2022

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IntroductionInsomnia is a major public health problem that determines the quality of life. Among the many causes of insomnia, psychological factors have an important influence on the process, duration of insomnia, help-seeking behavior, and treatment choice. Regarding medical treatment, zolpidem is always chosen to treat acute and transient insomnia due to its few side effects. Although some randomized controlled trials have verified its safety, zolpidem abuse and withdrawal reactions have been reported in recent years.Case reportA 25-year-old unmarried man with a college degree who worked as a graphic designer was referred and admitted to the inpatient ward for a chief complaint of “alternative episodes of lowering and elevation of mood for 10 years, overdosage use of zolpidem for two years.” He underwent a time-dependent withdrawal reaction after admission. It was characterized by rebound insomnia, anxiety, craving, skin paresthesia, influenza-like symptoms, tonic-clonic-type seizures, and hallucinations. At the 1-year follow-up, he did not exhibit any remaining withdrawal symptoms.DiscussionThe acute cessation of overdosage zolpidem use causes a series of withdrawal symptoms that manifest in chronological order. Additionally, long-term benzodiazepine exposure has potential influences on zolpidem dependence/tolerance. However, patients with a history of abuse or dependence, or mental disorders seem to be at risk of drug abuse. Clinicians should be alert to the potential for zolpidem dependence and addiction. Once the acute cessation of overdosage zolpidem use occurs, the potential of the withdrawal reaction needs to be considered and addressed properly.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Case report: Chronological symptom profile after cessation of overdose zolpidem in a patient with comorbid bipolar disorder—from anxiety, craving, paresthesia and influenza-like symptoms to seizures and hallucinations

et al. 2022

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“…Regarding development of tolerance and dependence to benzodiazepine-site ligands after prolonged administration, diverse effects at the molecular and cellular level have been described, including receptor desensitization and changes in the number and subunit composition of surface GABAA receptors, often leading to decreased ability of benzodiazepines to potentiate effects of GABA [17,[119][120][121][122][123][124].…”

Section: Effects Of Drugs Acting At Benzodiazepine Binding Sites At Gmentioning

confidence: 99%

GABA Receptors: Pharmacological Potential and Pitfalls

Jembrek¹,

Vlainić

2015

CPD

108

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Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, plays a key role in the regulation of neuronal transmission throughout the brain, affecting numerous physiological and psychological processes. Changes in GABA levels provoke disbalance between excitatory and inhibitory signals, and are involved in the development of numerous neuropsychiatric disorders. GABA exerts its effects via ionotropic (GABAA) and metabotropic (GABAB) receptors. Both types of receptors are targeted by many clinically important drugs that affect GABAergic function and are widely used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, aggressive behaviour, and other pathophysiological conditions and diseases. Of particular importance are drugs that modulate GABAA receptor complex, such as benzodiazepines, barbiturates, neuroactive steroids, intravenous and inhalational anesthetics, and ethanol. Molecular interactions and subsequent pharmacological effects induced by drugs acting at GABAA receptors are extremely complex due to structural heterogeneity of GABAA receptors and existence of numerous allosterically interconnected binding sites and various chemically distinct ligands that are able to bound to them. There is a growing interest in the development and application of subtype-selective drugs that will achieve specific therapeutic benefits without undesirable side effects. The aim of this review is to briefly summarize the key pharmacological properties of GABA receptors, and to present selected novel findings with the potential to open new perspectives in the development of more effective therapeutic strategies.

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“…This could presumably be associated with the development of tolerance, as it is with the continuous treatment [13,35] . The observed changes are not substantially different from those obtained after prolonged exposure of cells to high doses of classical benzodiazepines [14] .…”

Section: Wwwchinapharcom Vlainić J Et Almentioning

confidence: 99%

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

et al. 2012

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Aim: Zolpidem is a non-benzodiazepine agonist at benzodiazepine binding site in GABA A receptors, which is increasingly prescribed. Recent studies suggest that prolonged zolpidem treatment induces tolerance. The aim of this study was to explore the adaptive changes in GABA A receptors following short and long-term exposure to zolpidem in vitro. Methods: Human embryonic kidney (HEK) 293 cells stably expressing recombinant α1β2γ2s GABA A receptors were exposed to zolpidem (1 and 10 μmol/L) for short-term (2 h daily for 1, 2, or 3 consecutive days) or long-term (continuously for 48 h). Radioligand binding studies were used to determine the parameters of Conclusion:The results suggest that continuous, but not intermittent and short-term, zolpidem-exposure is able to induce adaptive changes in GABA A receptors that could be related to the development of tolerance and dependence.

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The effects of zolpidem treatment on GABAA receptors in cultured cerebellar granule cells: Changes in functional coupling

Cited by 8 publications

References 40 publications

Case report: Chronological symptom profile after cessation of overdose zolpidem in a patient with comorbid bipolar disorder—from anxiety, craving, paresthesia and influenza-like symptoms to seizures and hallucinations

Case report: Chronological symptom profile after cessation of overdose zolpidem in a patient with comorbid bipolar disorder—from anxiety, craving, paresthesia and influenza-like symptoms to seizures and hallucinations

GABA Receptors: Pharmacological Potential and Pitfalls

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

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